Compositions comprising pectin and ascorbic acid

ABSTRACT

Ascorbic acid compositions in the form of a powder and/or granules contain as principle components L-ascorbic acid and/or a pharmaceutically acceptable salt thereof, and a high molecular (300 kDalton or higher) pectin. The compositions are compressible into tablets with improved mechanical strength and hardness.

The present invention relates to a composition in the form of a powderand/or granules, which contain as principal components L-ascorbic acidand/or a pharmaceutically acceptable salt thereof, and high molecularpectin. The composition according to the present invention is directlycompressible into tablets with good taste, improved mechanical strengthand hardness, with excellent color stability and is free of sugar andstarch. The addition of adjuvants and excipients to the composition forproducing tablets is optional.

Compositions comprising L-ascorbic acid and/or a pharmaceuticallyacceptable salt thereof and pectin, as well as tablets manufacturedusing such compositions have been described in European PatentApplication No.1 110 550 A2.

It has now been found that tablets manufactured using a compositioncomprising L-ascorbic acid and/or its salts, and high molecular pectinshow improved hardness as compared to tablets manufactured usingconventional pectin of lower molecular weight.

Thus, in one aspect the invention relates to a composition in the formof a powder or granules comprising:

-   -   (a) L-ascorbic acid and/or a pharmaceutically acceptable salt        thereof,    -   (b) high molecular pectin and, optionally,    -   (c) adjuvants and excipients.

The term “high molecular pectin” as used herein denotes pectin having anaverage molecular weight of about 300 kDalton or higher. The preferredhigh molecular pectins are those having an average molecular weight offrom about 300 kDalton to about 400 kDalton, particularly 350 kDalton.Such pectins can be obtained as disclosed in U.S. Pat. No. 6,143,337(inventors: Marshall L. Fishman and Hoa K. Chau, assignors to The UnitedStates of America as represented by the Secretary of Agriculture) thecontents of which is incorporated herein by reference. The averagemolecular weight is determined by size exclusion chromatography having amulti angle laser light scattering detector as described in U.S. Pat.No. 6,143,337. However, pectins of higher molecular weight, e.g. up to2000 kDalton can be used also in the present invention. Pectins of suchmolecular weight can be obtained e.g. from Asteraceae plants, especiallycichory and Jerusalem artichoke, see International patent application WO99/03892. Fractions of the desired high molecular weight can be obtainedfrom such pectins by membrane filtration, e.g. using polyethersulfone orcomposite regenerate cellulose membranes as supplied by MilliporeCorporation, Bedford, Mass. 01730, USA, under the trade name Pellicon®Tangential Flow Filtration Cassettes.

In accordance with the present invention, the high molecular pectin ispreferably used in quantities within the range of about 0.1% to about10% by weight, preferably in quantities of about 0.5% to about 5% byweight and most preferably in quantities of about 0.5% to about 2% byweight, calculated to the total weight of the composition thereof.Experiments have shown that a composition consisting of 95-99% by weightof L-ascorbic acid and/or the pharmaceutically acceptable salt thereofand 5-1% by weight of pectin, the two components totalling 100% byweight, i.e. with no other components present, yield tablets of verygood quality and excellent color stability.

Adjuvants may optionally be added. Suitable adjuvants are for examplestarch, HPMC, polyols. Preferably no adjuvants are added.

The composition of this invention may be produced by any method knownper se for the production of powders or granules. Preferred arefluidized-bed granulation, high-shear granulation, extrusion,spray-drying and wet granulation.

For obtaining the composition of the present invention by spray-dryingit is convenient to prepare an aqueous slurry of all the components. Theslurry has preferably a solid content of about 10 to 70% by weight, andpreferably about 30 to 70% by weight. The slurry is then spray-dried ina manner known per se.

For obtaining the composition of the present invention by fluidized-bedgranulation it is convenient to use a known fluidized-bed granulatingapparatus which comprises a fluidized-bed drying device fitted withspray means. Preferably the L-ascorbic acid and/or a pharmaceuticallyacceptable salt thereof form the fluidized bed, which is fluidized byair or an inert gas, e.g. nitrogen. The pectin, as well as optionaladjuvants, dissolved in an appropriate amount of water and sprayed inthe form of an atomized mist onto the fluidized particles in such amanner that the granulating and drying operations is accomplished in asingle step. The granulating process is continued until the desiredamount of the pectin binder has been deposited onto the fluidizedparticles. The granules are sieved to remove the fractions of granuleswhich are either too large or too small. Preferably, the particle sizeof the granules is within 100 and 1000 micron, more preferably between125 and 850 microns. While the so-obtained granules are substantiallydry they may contain a very small percentage of water depending on theamount of pectin. For 1% pectin, the moisture content is about 0.2% orless. For 5% pectin, the moisture content may be as high as 1%.

The composition thus obtained may be compressed into tablets withconventional tabletting methods and machinery. Optionally the powder orthe granules may further be mixed with a lubricant or a mixture oflubricants and then compressed into tablets. If additional lubricant isused it is preferably selected from the group of stearic acid or themagnesium or calcium salt thereof, or glyceryl behenate 45 (Compritol888 ATO), preferably in an amount of about 0.5 to 4% by weight,calculated to the total weight of the composition. Or the compositionmay be mixed with excipients. Examples for excipients are dextrinizedsucrose (Di Pac sugar), microcrystalline cellulose or starch.

A single tablet as obtained according to the present invention containspreferably 50 mg to 1500 mg, preferably 500 mg to 1000 mg of L-ascorbicacid and/or the pharmaceutically acceptable salt thereof, correspondingto an appropriate daily doses of vitamin C. The following Exampleillustrates the invention further.

EXAMPLE

Two pectins having different molecular weight were investigated. One hadan average molecular weight of 200 kDalton (USP/100, lot 02635-0, CPKelco, San Diego, USA) and another had an average molecular weight ofabout 350 kDalton. The 350 kDalton pectin was a sample from the UnitedStates Department of Agriculture and was prepared by the processdisclosed in U.S. Pat. No. 6,143,337.

A 1.9% pectin solution was prepared by dissolving pectin in water.Sodium ascorbate powder (F. Hoffmann—La Roche AG, Switzerland, Ave.particle size ca. 50 microns) was placed in a Glatt Fluidized-Bedgranulator (Model Uniglatt, Switzerland) and sprayed with a fine mist ofthe pectin solution, which was kept at about 50° C. during spraying. Thegranulation conditions were as follows:

-   -   L-Sodium ascorbate: 400 g    -   1.9% Pectin solution: 213 g    -   Pectin solution spraying rate: 9.9 g/minute    -   Inlet air temperature: 80° C.    -   Outlet air temperature: 40° C.    -   Product temperature: 32° C.

The granules had a particle size distribution as shown in Table 1. Thegranules (125-850 micron fraction) were mixed with the excipients asshown in Table 2 and then compressed into 700-mg tablets with a diameterof 12 mm to tablets of various thickness. The hardness of the tabletswas determined and is shown in Table 3. TABLE 1 Particle SizeDistribution, % Particle Size (Microns) >850 >710 >500 >355 >250 >125<125 Pectin USDA (C99-482) 8.5 6.2 17.2 20.8 21.0 20.2 6.1 Pectin USP100CP Kelco 15.3 6.1 14.1 16.8 19.8 21.0 7.0 (lot 02635-0)

TABLE 2 Parts Granule sample prepared 100 from the example RocheAscorbic Acid 90% 65.84 Granulation White Di Pac sugar 249.04 Compritol888 ATO 8.48

TABLE 3 CP Kelco Pectin Pectin USDA USP100 (C99-482) (lot 02635-0) Mol.Weight: 350 Mol. Weight: 200 kDalton kDalton Tablet Tablet Tablet TabletThickness Hardness Thickness Hardness mm N mm N 4.30 146.6 4.31 134.34.15 202.3 4.16 175.5 4.05 238.6 4.04 208.5 3.98 255.0 3.98 234.8 3.94268.6 3.93 243.1 3.97 297.4 n.a. n.a.n.a.: not availableThe results of Table 3 show that the use of the high molecular pectin(MW 350 kDalton) resulted in tablets of substantially higher hardnesswhen the same or substantially the same tabletting parameters wereapplied.

1. A composition in the form of a powder or granules comprising: (a)L-ascorbic acid and/or a pharmaceutically acceptable salt thereof, (b)high molecular pectin.
 2. A composition according to claim 1, whereinthe high molecular pectin has an average molecular weight of about 300kDalton or higher.
 3. A composition according to claim 1, wherein thehigh molecular pectin has an average molecular weight of about 300kDalton to about 400 kDalton.
 4. A composition according to claim 1,wherein the high molecular pectin has an average molecular weight ofabout 350 kDalton.
 5. A composition according to claim 1 wherein theL-ascorbic acid and/or a pharmaceutically acceptable salt thereof issodium L-ascorbate.
 6. A composition according to claim 1, wherein thepectin is present in quantities within the range of about 0.1% to about10% by weight, calculated on the total weight of the composition.
 7. Acomposition according to claim 1, wherein the pectin is present inquantities within about 0.5% to about 2% by weight, calculated on thetotal weight of the composition.
 8. A composition according to claim 1,wherein said composition consists of 95-99% by weight of L-ascorbic acidand/or a pharmaceutically acceptable salt thereof and 5-1% by weight ofpectin, the two components totaling 100% by weight.
 9. A compositionaccording to claim 1 in the form of a compressed tablet.
 10. (Canceled).11. A composition according to claim 1 further comprising an adjuvant orexcipient.
 12. A composition according to claim 2 wherein the L-ascorbicacid and/or a pharmaceutically acceptable salt thereof is sodiumL-ascorbate.
 13. A composition according to claim 3 wherein theL-ascorbic acid and/or a pharmaceutically acceptable salt thereof issodium L-ascorbate.
 14. A composition according to claim 4 wherein theL-ascorbic acid and/or a pharmaceutically acceptable salt thereof issodium L-ascorbate.
 15. A composition according to claim 11 wherein theL-ascorbic acid and/or a pharmaceutically acceptable salt thereof issodium L-ascorbate.
 16. A composition according to claim 5, wherein thepectin is present in quantities within the range of about 0.1% to about10% by weight, calculated on the total weight of the composition.
 17. Acomposition according to claim 11, wherein the pectin is present inquantities within the range of about 0.1% to about 10% by weight,calculated on the total weight of the composition.
 18. A compositionaccording to claim 5, wherein the pectin is present in quantities withinabout 0.5% to about 2% by weight, calculated on the total weight of thecomposition.
 19. A composition according to claim 5, wherein saidcomposition consists of 95-99% by weight of L-ascorbic acid and/or apharmaceutically acceptable salt thereof and 5-1% by weight of pectin,the two components totaling 100% by weight.
 20. A composition accordingto claim 5 in the form of a compressed tablet.